Delayed-Release Glucocorticoid treatment of Rheumatoid Disease

ABSTRACT

The present invention refers to the treatment of a rheumatic disease and/or osteoarthritis by administering a delayed-release dosage form of a glucocorticoid to a subject in need thereof.

The present invention refers to the treatment of a rheumatic diseaseand/or osteoarthritis by administering a delayed-release dosage form ofa glucocorticoid to a subject in need thereof.

BACKGROUND OF THE INVENTION

Role of Low-Dose Corticoid Therapy in Clinical Practice

Diseases of rheumatoid nature like rheumatoid arthritis (RA) arechronic, autoimmune disorders in which inflammation of the synovialjoint lining is accompanied by joint pain and stiffness and usuallyleads to bone and joint destruction, deformity, disability, and evendeath. RA affects about 1% of the population and is 2 to 3 times morecommon in women than in men (CPMP/EWP/556/95). Early diagnosis,suppression of inflammation, and aggressive treatment strategies areregarded as important requisites for a favorable outcome (Pincus 2005).Glucocorticoids are widely used to treat the disease and are oftenadministered in combination with other drugs, especiallydisease-modifying antirheumatic drugs (DMARDs) and non-steroidalanti-inflammatory drugs (NSAIDs) (Bijlsma 2003). Prednisone,prednisolone and methylprednisolone are among the most commonglucocorticoids for the treatment of RA.

Use and types of oral corticoid RA therapy differ according to regionand published estimates vary. According to one source, in 2002 about 40to 50% of patients in France, Germany, Italy and Spain received suchtherapy compared to about 20% in the United Kingdom (UK). Prednisone wasthe most common corticoid in France, Italy and Spain (94%, 59% and 43%of treated patients, respectively) whereas prednisolone was the mostcommon in Germany and the UK (50 and 100%, respectively). A study in 150patients who attended a US clinic during the period 1999 to 2001 showedthat 144 (96%) patients took prednisone in combination with DMARDs (86%)or alone (10%) (Pincus 2005).

Glucocorticoids have a broad spectrum of anti-inflammatory andimmunosuppressive effects. They act by inhibiting leukocyte traffic;interfering with functions of leukocytes, fibroblasts, and endothelialcells; and suppressing the synthesis and actions of inflammatorycytokines including interleukin-6 (IL-6) (Buttgereit 2005). When theywere first introduced, glucocorticoids were administered to RA patientsfor long periods at high doses exceeding 10 mg/day prednisone orequivalent. These high-dose, long-term regimens were highly effectivebut were associated with pleiotropic effects and unacceptable adversereactions. This led to the development of low-dose regimens in order toreduce the incidence of side effects and optimized the benefit:riskratio (Buttgereit 2005). High corticoid doses are now only consideredsuitable for short-term therapy in special cases (e.g. for treatment ofa severe flare of RA). Decreases in prescribed corticoid dose areillustrated by an evaluation of patients who attended a US clinicbetween 1984 and 1986 (1985 cohort) or between 1999 and 2001 (2000cohort) (Pincus 2005). The mean prednisone dose was 7.8 mg/day in 1985compared to 4 mg/day in 2000, with median doses of 5 and 4 mg/day,respectively.

Long-term, low-dose, corticoid therapy (defined as daily doses of ≦10 mgprednisone or equivalent) is currently recognized as an important partof standard treatment for RA (ACR guideline, Conn 2001). Below 10 mg thedaily dose should be decreased stepwise until the lowest, stilleffective dose for disease control is reached. In addition to providingimmediate relief of symptoms such as morning stiffness and pain, thelow-dose corticoid regimen also prevents progression of disease. Severalrandomized studies performed since the mid-1990s have shown thatlow-dose prednis(ol)one slows the rate of joint damage (as measured byradiographic images) in patients with early, active RA. In adouble-blind, placebo-controlled study, 7.5 mg/day prednisolone reducedjoint destruction when given for 2 years in combination with otherstandard RA treatments (Kirwan 1995). When prednisolone was stopped,joint destruction returned to the same level as in the control group(Hickling 1998). In a more recent double-blind, placebo-controlledstudy, prednisone (10 mg/day) slowed progression of joint damage overperiods of 2 and 5 years in patients who had not been pretreated withDMARDs (van Everdingen 2002, Jacobs 2005). In a double-blind,placebo-controlled study (Wassenberg 2005) and an open-label,DMARD-controlled study (Svensson 2005), prednisolone at doses of 5 and7.5 mg/day, respectively, decreased radiographic progression when givenin combination with DMARDs for 2 years. The increasing evidence for thedisease-modifying effects of low-dose corticoid treatment has certainlycontributed to renewed interest in this treatment regimen and increaseduse in clinical practice.

Safety of Low-Dose Long-Term Corticoid Therapy

Soon after glucocorticoids were introduced for the treatment of RA inthe 1950s it became apparent that long-term use of high doses wasassociated with clinically significant side effects that includedosteoporosis, glucose intolerance, infections, peptic ulcers andgastrointestinal bleeding, cataracts and glaucoma, as well asatherosclerotic disease. Several clinical studies and literature reviewshave been performed to assess the safety profile of low-dose, long-termcorticoid therapy. It is generally agreed that side effects can bereduced by using as low a dose as possible for each individual patient.One study that compared RA patients with and without prednisonetreatment concluded that long-term prednisone use at doses ≧5 mg/day wasassociated with the dose-dependent development of specific AEs (Saag1994). However, this study was retrospective with historical casecontrols and included prednisone doses up to 15 mg/day. A working groupof rheumatologists and experts from other therapeutic areas has recentlyconducted a comprehensive literature review of the adverse effects oflow-dose (≦10 mg/day prednisolone equivalent), long-term glucocorticoidtherapy by a primary search of textbooks and review papers (da Silva2006). Their review also included analysis of data from 4 prospective,randomized, controlled studies in which prednisolone (5 to 10 mg/day)was given to RA patients for 2 years (Capell 2004, Kirwan 1995, vanEverdingen 2002, Wassenberg 2005). Common side effects seen at highdoses were not observed at low doses or were less frequent. The expertsconcluded that “the overall fear of glucocorticoid toxicity in RA, asquoted in textbooks and review articles, is probably overestimated basedon observations with higher dose therapy. The balance of risks andbenefits of low-dose therapy clearly differs from that of medium- andhigh-dose therapy . . . ”. Osteoporosis, obesity, hypertension, familyhistory of diabetes or glaucoma were listed as risk factors requiringmore careful observation. In addition to osteoporosis, adverse effectsthat may need regular checks were defined as Cushingoid syndrome,adrenal crisis of corticoid withdrawal, new onset of diabetes mellitus,worsening of glycemia control in patients with diabetes mellitus,cataracts, glaucoma, peptic ulcer (in combination with NSAIDs), andhypertension.

Delayed-Release Prednisone Tablets

Patients with active RA suffer from clinical signs and symptoms thatinclude joint stiffness, pain, and swelling. Patients have assessedthese symptoms (and related factors such as disability and mobility) asbeing important outcomes of RA treatment (Ah/men et al. 2005, Carr etal. 2003, Hewlett et al. 2005). Clinical symptoms vary during the dayand are more severe early in the morning after awakening than in theafternoon or evening (Cutolo et al. 2003, Cutolo and Masi 2005). Indeed,morning stiffness is such a typical symptom of RA that it has become astandard diagnostic criterion for the disease (Arnett et al. 1988, ACRGuideline 2002).

The mechanisms responsible for the circadian variation of RA symptomsare complex and involve the HPA axis and endogenous inflammatorymediators. Inflammation causes increased production of inflammatorycytokines. In comparison with healthy subjects, RA patients thereforehave higher serum concentrations of interleukins (IL), especially IL-6,and tumor necrosis factor-alpha (TNF-α) and levels display a pronouncedcircadian rhythm, with higher night-time concentrations that peak at02:00 to 06:00 (Arvidson et al. 1994; Crofford 1997; Cutolo 2003, 2005).

Increased levels of IL-6 are produced in response to inflammation butIL-6 is a potent activator of the HPA axis and stimulates the release ofcortisol from the adrenal cortex to counteract the inflammation (Cutolo2005, Mastorakos 2000). In RA patients, it seems that the response ofthe permanently stimulated HPA axis is inadequate and levels ofendogenous cortisol are insufficient to combat the inflammation(Gudbjörnsson 1996). Administration of exogenous glucocorticoidsacts—among other therapeutic effects—as a replacement therapy andsupplements the inadequate levels of endogenous cortisol (Cutolo 2005).

Endogenous cortisol and exogenous therapeutic glucocorticoids inhibitthe synthesis of IL-6 and other pro-inflammatory cytokines. In thiscontext, prednis(ol)one and methylprednisolone are ideally suitedexogenous corticoid due to its comparatively short half-life of 3-4 h.Low-dose oral prednis(ol)one or methylprednisolone are usually given forsymptomatic relief as a single morning dose to minimize potentialinterference with the HPA axis. However, in order to provide optimalrelief of morning stiffness and joint pain it has been proposed that thedrug should be given shortly before the expected nocturnal increase ofIL-6. A randomized study has investigated the efficacy of standard IR(Immediate Release) low-dose prednisolone (5 or 7.5 mg/day) given at02:00 or at 07:30 for 4 days in 26 patients with active RA who werebeing treated with standard anti-rheumatic drugs (predominantly NSAIDs)but who had not received glucocorticoids in the 3 months before thestudy (Arvidson et al. 1997). Night-time administration of prednisoloneat 02:00 resulted in highly statistically significant improvements inmorning stiffness, joint pain, as well as suppression of serumconcentrations of IL-6 (p<0.01). Much smaller effects (p<0.05) were onlyobserved for morning stiffness and IL-6 concentrations afterconventional morning dosing at 07:30. The authors concluded that lowdoses of glucocorticoids improved acute RA symptoms if they wereadministered before the circadian flare of increased IL-6 synthesis andinflammatory activity. However, it remained unclear what would happen tothe patients if they would be treated for a longer period of time.

Karatay et al investigated in 2002 the administration of an IR low-doseprednisone tablet over a period of 6 months at 02:00 vs 07:30. Theresults were disappointing because a difference in morning stiffnesscould not be observed. One explanation of this could be that the shortterm effects observed by Arvidson disappear after several days or weeksof therapy. Thus, the effects on long term night time administration ofglucocorticoids remained unclear.

Furthermore, all patients in both study (Arvidson 1997; Karatay 2002)were corticoid naïve. Thus, the question has arisen, how low-dosenight-time prednisone would work in patients already pre-treated withlow-dose corticoids and what would happen if they would get thenight-time dose over a longer time with a higher compliance rate.

Although administration of glucocorticoids at 02:00 resulted in improvedefficacy in one of two studies, in practice this would be highlyinconvenient for the patient and likely to result in poor quality ofsleep and/or compliance.

U.S. Pat. No. 5,792,476 describes a pharmaceutical composition forperoral administration for rheumatoid arthritis, which comprises aglucocorticoid as active ingredient and which leads to release in thesmall intestine. The composition is a granulate which is laminated withan inner layer which is resistant to a pH of 6.8, and with an outerlayer which is resistant to a pH of 1.0.

U.S. Pat. No. 6,488,960 describes a pharmaceutical dosage form forcontrolled release of corticoids, reference being made to theformulations described in U.S. Pat. No. 5,792,476.

WO 01/08421 describes a tablet having a core which is coated by at leasttwo layers, one of which completely encloses the other. The coatinglayers can be produced by spray coating and/or pressing.

WO 01/68056 discloses a pharmaceutical preparation having a releaseprofile with a time delay, comprising a core and at least onehydrophilic or lipophilic coating surrounding the core, where thecoating is slowly swollen, dissolved, eroded or changed in its structurein another way through the water present in the release medium, so thatthe core or parts of the core become accessible to the release medium.The coating may be formed for example as pressed coating.

WO 02/072034 discloses a pharmaceutical dosage form for delayed release,having a core which comprises as active ingredient a glucocorticoid anda material which brings about delayed release and includes at least onenatural or synthetic gum.

WO 2004/093843 discloses a tablet with a specific core geometry torelease the active ingredient in a specific delayed release manner.

WO 2006/027266 discloses a pharmaceutical dosage form with site- andtime controlled gastrointestinal release of an active agent,particularly a corticosteroid. The pharmaceutical dosage form ispreferably a coated tablet having a core comprising the corticosteroidand a swellable/disintegration adjuvant, and an inert outer coating. Thecoating is compressed at a pressure chosen to result in the release ofthe corticosteroid at a predetermined position in the gastrointestinaltract.

SUMMARY OF THE INVENTION

The present inventors have carried out a clinical study in order to testthe efficacy of a delayed-release prednisone tablet compared to astandard immediate-release tablet. It was found that long-termadministration of the delayed-release prednisone tablet shows asurprisingly increased efficacy compared to the treatment with astandard immediate-release prednisone tablet.

Thus, a first aspect of the invention refers to the use of adelayed-release dosage form of a corticosteroid for the manufacture of amedicament for the long-term treatment of a rheumatic disease and/orosteoarthritis.

A further aspect of the invention refers to the use of a delayed-releasedosage form of a glucocorticoid for the manufacture of a medicament forthe treatment of a rheumatic disease and/or osteoarthritis in

-   -   (i) patients with severe diseases,    -   (ii) patients with moderate diseases,    -   (iii) patients with mild diseases,    -   (iv) patients with short disease duration (<2 years),    -   (v) patients with mid-term disease duration (2-5 years) or    -   (vi) patients with long-lasting disease duration (>5 years).

Still a further aspect of the present invention refers to the use of adelayed-release dosage form of a glucocorticoid for the manufacture of amedicament for the treatment of a rheumatic disease and/orosteoarthritis in

-   -   (i) patients with severe, long lasting morning stiffness    -   (ii) patients with moderate morning stiffness;    -   (iii) patients with mild morning stiffness;    -   (iv) patients with severe, long lasting pain    -   (v) patients with moderate pain;    -   (vi) patients with mild pain.

Still a further aspect of the present invention refers to the use of adelayed-release dosage form of a glucocorticoid for the manufacture of amedicament for the treatment of a rheumatic disease and/orosteoarthritis in

-   -   (i) patients with high Interleukin 6 levels;    -   (ii) patients with medium Interleukin 6 levels or    -   (iii) patients with low Interleukin 6 levels.

Still a further aspect of the present invention is the use of adelayed-release dosage form of a glucocorticoid for the manufacture of amedicament for the treatment of a rheumatic disease and/orosteoarthritis in

-   -   (i) patients who have been pre-treated with an immediate release        dosage form of a glucocorticoid,    -   (ii) patients who are refractory to treatment with an immediate        release dosage form of a glucocorticoid, or    -   (iii) glucocorticoid naïve patients.

Still a further aspect of the present invention refers to the use of adelayed-release dosage form of a glucocorticoid for the manufacture of amedicament for the treatment of rheumatic diseases in

-   -   (i) patients who have been pre-treated with other medicaments        like a NSAID, a DMARD, a TNFα inhibitor, an IL-6 inhibitor        and/or an analgetic agent or any combination thereof, or    -   (ii) patients who have not been pre-treated with any other        medicaments like a NSAID, a DMARD, a TNFα inhibitor, an IL-6        inhibitor and/or an analgetic agent.

Still a further aspect of the present invention refers to the use of adelayed-release dosage form of a glucocorticoid for the manufacture of amedicament for the treatment of a rheumatic disease and/orosteoarthritis in combination with at least one further medicament whichis a NSAID, a DMARD, a TNFα inhibitor, an IL-6 inhibitor and/or ananalgetic agent.

Still a further aspect of the present invention is the use of adelayed-release dosage form of a glucocorticoid for the manufacture of amedicament for the treatment of a rheumatic disease and/orosteoarthritis without any further medicament.

Still a further aspect of the present invention is the use of adelayed-release dosage form of a glucocorticoid for the manufacture of amedicament for treatment of a rheumatic disease and/or osteoarthritis incombination with reduced doses of at least one further medicament whichis a NSAID, a DMARD, a TNFα inhibitor, an IL-6 inhibitor and/or ananalgetic agent.

Still a further aspect of the present invention is the use of adelayed-release dosage form of a glucocorticoid for the manufacture of amedicament for the treatment of ankylosating spondylitis, polymyalgiarheumatica and/or osteoarthritis.

Still a further aspect of the present invention is the use of adelayed-release dosage form of a glucocorticoid for the manufacture of amedicament for the treatment of morning stiffness, pain and/orinflammation parameters such as release of cytokines, e.g. in arheumatic disease and/or osteoarthritis.

Still a further aspect of the present invention is a method for thetreatment of a patient suffering from signs and symptoms of anunderlying rheumatic disease and/or osteoarthritis, which comprisesadministering to said patient an effective amount of a glucocorticoidcontained in a delayed-release dosage form, wherein said treatment isadministered once daily for at least about two weeks.

Still a further aspect of the present invention is a method for thetreatment of a patient suffering from morning stiffness and pain due toan underlying rheumatic disease and/or osteoarthritis, which comprisesadministering to said patient an effective amount of a glucocorticoidcontained in a delayed-release dosage form, wherein said treatment isadministered once daily for at least about two weeks.

Still a further aspect of the present invention is a method for thetreatment of a patient having circadian fluctuations in Interleukin 6levels due to underlying inflammation, which comprises administering tosaid patient an effective amount of a glucocorticoid contained in adelayed-release dosage form, wherein said treatment is administered oncedaily for at least about two weeks, and wherein said treatment isadministered such that the glucocorticoid is released at or before thetime when the patient's Interleukin 6 level is at a daily peak.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows duration of Morning Stiffness: Relative Change fromBaseline in % (SEM) per week of treatment in the ITT population.

FIG. 2 shows duration of Morning Stiffness: Relative Change fromBaseline in % (SEM) per month of treatment in the ITT population.

FIG. 3 shows IL 6 values (median) under treatment of Prednisone delavedrelease tablets.

DETAILED DESCRIPTION OF THE INVENTION

The present invention refers to the use of a delayed-release dosage formof a glucocorticoid. The release of the active ingredient is preferablydelayed for a time period of 2-10 hours after intake, preferably 2-6,more preferably 3-5 hours after intake the active ingredient may bereleased in the upper sections of the intestine and/or in the lowersections of the intestine. More preferably, the active ingredient isreleased in the upper sections of the intestine within a period of 2-6hours. The delayed-release dosage form is preferably administered to thepatient at or before bedtime, more preferably in the evening, e.g. fromabout 9:00 pm to about 11:00 pm. Because inflammation is accompaniedwith circadian fluctuations in the concentration of pro-inflammatorycytokines (such as Interleukin-6) which peaks during sleeping hours,bedtime administration allows an efficacious concentration of the activeingredient to be present when such concentration peaks.

The delayed-release dosage form is preferably a tablet, e.g. asdescribed in WO 2006/027266, which is herein incorporated by reference.The dosage form preferably comprises

-   -   (a) a core having at least one glucocorticoid-active ingredient        and having at least one swellable adjuvant and/or a disintegrant        such that the active ingredient is rapidly released from the        dosage form when the core is contacted with gastrointestinal        fluids, and    -   (b) an inert, e.g. a non-soluble and non-swellable coating        pressed onto the core, said coating being capable of preventing        substantial release of the active ingredient for a defined time        period following ingestion of the dosage form.

The inert coating initially prevents release of the active ingredient orthe active ingredient combination over an exactly defined period, sothat no absorption can occur. The water present in the gastrointestinaltract penetrates slowly in through the coating and, after a time whichis previously fixed by the pressure for compression, reaches the core.The coating ingredients show neither swelling nor diluting of parts ofthe coating. When the core is reached, the water penetrating in is veryrapidly absorbed by the hydrophilic ingredients of the core, so that thevolume of the core increases greatly and, as a consequence thereof, thecoating completely bursts open, and the active ingredient and the activeingredient combination respectively is released very rapidly.

A particularly advantageous embodiment of this press-coateddelayed-release tablet is achieved when a previously compressed coretablet is subsequently compressed with a multilayer tablet press to apress-coated tablet.

The tablet coating typically consists of the following materials inorder to achieve a delayed release profile:

-   -   polymer or copolymer of acrylic acid, methacrylic acid etc.        (e.g. Eudragits or Carbopol),    -   cellulose derivatives such as hydroxypropylmethylcellulose,        hydroxypropylcellulose, carboxymethylcellulose, ethylcellulose,        cellulose acetate,    -   polyvinyl alcohol,    -   polyethylene glycol,    -   salts of higher fatty acids, esters of monohydric or polyhydric        alcohols with short-, medium- or long-chain, saturated or        unsaturated fatty acids. Specifically, stearic acid        triglycerides (e.g. Dynersan) or glycerol behenate (e.g.        Compritol) are used.

In addition, further adjuvants should also be added to these materialsso that the tablet coating can be compressed. Typically used here arefillers such as lactose, various starches, celluloses and calciumhydrogen phosphate or di-basic calcium phosphate. The glidant used isnormally magnesium stearate, and in exceptional cases also talc andglycerol behenate. A plasticizer is often also added to the coatingmaterial, preferably from the group of polyethylene glycol, dibutylphthalate, diethyl citrate or triacetin.

In order to achieve an optimal release profile, the tablet core mustalso fulfil certain tasks and exhibit certain properties. Thus, afterthe lag phase has elapsed, a rapid release profile is achieved iftypical disintegrants are added to the inner core, which are derived forexample from the group of the following substances: cellulosederivatives, starch derivatives, crosslinked polyvinylpyrrolidone. Theuse of a blowing agent, for example resulting from a combination of aweak acid and a carbonate or bicarbonate, may also promote rapidrelease. The tablet core typically consists additionally of matrix orfilling ingredients (e.g. lactose, cellulose derivatives, calciumhydrogen phosphate or other substances known from the literature) andlubricant or glidant (usually magnesium stearate, in exceptional casesalso talc and glycerol behenate).

The size of the core tablet preferably should not exceed 6 mm(preferably 5 mm) in diameter, because otherwise the press-coated tabletbecomes too large for convenient ingestion. As a result thereof, thedosages of the active ingredients are in the range from 0.1 to 50 mg,very particularly between 1 and 20 mg.

The in vitro release profile of the dosage form according to theinvention is preferably such that less than 5% of the active ingredientis released during the lag phase. After the release phase has started,preferably ≧80%, particularly preferably ≧90%, of the active ingredientis released within one hour. More preferably, the delayed-release dosageform has a dissolution time of equal to or less than about 2 hours afterthe lag time has been reached). The in vitro release is preferablydetermined using the USP paddle dissolution model in water.

The employed active ingredients are derived from the group ofglucocorticoids and all show comparable physicochemical properties. Suchinclude cortisone, hydrocortisone, prednisone, prednisolone,methylprednisolone, budesonide, dexamethasone, fludrocortisone,fluocortolone, cloprednole, deflazacort, triamcinolone, or thecorresponding pharmaceutically acceptable salts and/or esters thereof.This applies in particular to prednisone, prednisolone,methylprednisolone, budesonide, dexamethasone, fluocortolone,cloprednole, and deflazacort or the corresponding pharmaceuticallyacceptable salts and/or esters thereof.

In the present case of the delayed-release tablet, the followingcombination of core materials and coating materials has proved to beparticularly suitable for achieving a time- and site-controlled releasewith exclusion of pH and food influences:

The coating preferably comprises:

-   -   hydrophobic, waxy substances with an HLB value of less than        about 5, preferably around 2. Carnauba wax, paraffins, cetyl        ester waxes are preferably employed therefor. Glycerol behenate        has proved to be particularly suitable.    -   The use of about 20-60%, in particular about 30-50%, in the        coating has proved to be very advantageous;    -   non-fatty, hydrophobic filling materials such as calcium        phosphate salts, e.g. dibasic calcium phosphate. The use of        about 25-75% of these filling materials, in particular of about        40-60%, in the coating has proved to be very advantageous here;    -   in addition, the tablet coating preferably also consists of        binders, e.g. polyvinylpyrrolidone (PVP), typically in        concentrations of about 4-12%, specifically about 7-10%, and        glidants such as magnesium stearate, in concentrations of about        0.1-2%, in the specific case of about 0.5-1.5%. Colloidal        silicon dioxide can for example be used as flow regulator,        normally in concentrations of about 0.25-1%. In addition, to        distinguish different dosages, a colorant can be added to the        tablet coating, preferably an iron oxide pigment in        concentrations of about 0.001-1%.

The core tablet preferably comprises:

-   -   an active ingredient or an active ingredient combination from        the group of glucocorticoids, preferably prednisone,        prednisolone, methylprednisolone, budesonide, dexamethasone,        fludrocortisone, fluocortolone, cloprednole, deflazacort, and        triamcinolone, and the corresponding salts and esters thereof.        The dosages of the active ingredients are in the region of about        0.1-50 mg, very especially between about 1 and 20 mg;    -   in addition, the core tablet preferably comprises a filler such        as, for example, lactose, starch derivatives or cellulose        derivatives. Lactose is preferably employed. The filler is        typically present in concentrations of about 50-90%,        specifically of about 60-80%. A disintegrant is additionally        present and is typically crosslinked PVP or sodium        carboxymethylcellulose, typically in concentrations of about        10-20%. It is additionally possible for a binder, e.g. PVP, to        be present, typically in concentrations of about 2-10%,        specifically of about 5.5-9%, and a lubricant such as magnesium        stearate, in concentrations of about 0.1-2%, in the specific        case of about 0.5-1.5%. Colloidal silicon dioxide is normally        used as flow regulator, normally in concentrations of about        0.25-1%. It is additionally possible, for visually        distinguishing the core from the coating, to add a colorant,        preferably an iron oxide pigment in concentrations of about        0.01-1%.

Preferably, the delayed-release dosage form is administered as along-term treatment to a subject in need thereof for a time sufficientto reduce and/or abolish the disease and/or disease symptoms. The longterm treatment usually comprises daily administration of the medicamentfor an extended period of time, e.g. for at least two weeks, preferablyfor at least 4 weeks, more preferably for at least 8 weeks, even morepreferably for at least 12 weeks, and most preferably for at least 6months or at least 12 months.

According to the present invention refers to the novel treatment ofgroups of patients suffering from rheumatic diseases and/orosteoarthritis. These patient groups are selected from:

-   -   (i) patients with severe diseases characterized by a Disease        Activity Score (DAS) of >5.1 (Le Loet 2006) and/or a Physicians        Assessment;    -   (ii) patients with moderate diseases characterized by a Disease        Activity Score (DAS) of >3.2 but <5.1 and/or a Physicians        Assessment;    -   (iii) patients with mild diseases characterized by a Disease        Activity Score (DAS) of <3.2 and/or a Physicians Assessment;    -   (iv) patients with short disease duration of less than 2 years,    -   (v) patients with mid-term disease duration of 2-5 years, and    -   (vi) patients with long-lasting disease duration of more than 5        years.

Further patient groups may be selected from:

-   -   (i) patients with severe, long lasting morning stiffness        characterized by a duration of morning stiffness >180 min,    -   (ii) patients with moderate morning stiffness between 100 and        180 min,    -   (iii) patients with mild morning stiffness of less than 100 min,    -   (iv) patients with severe, long lasting pain characterized by a        VAS scale with >70 mm,    -   (v) patients with moderate pain characterized by a VAS scale        with >50-70 mm,    -   (vi) patients with mild pain characterized by a VAS scale with        <50 mm.

Further patient groups may be selected from:

-   -   (i) patients with high Interleukin 6 levels, e.g. more than 3000        IU/I;    -   (ii) patients with medium Interleukin 6 levels, e.g. between        3000 and 1000 IU/I;    -   (iii) patients with low Interleukin 6 levels, e.g. less than        1000 IU/I.

Further patient groups may be selected from:

-   -   (i) patients who have been pre-treated with an immediate release        dosage form of a glucocorticoid;    -   (ii) patients who are refractory to treatment with an        immediate-release dosage form of a glucocorticoid, and    -   (iii) glucocorticoid naive patients.

Further patient groups may be selected from:

-   -   (i) patients who have been pre-treated with other medicaments        like a NSAID, a DMARD, a TNFα inhibitor and/or an analgetic        agent or any combination thereof, and    -   (ii) patients who have not been pre-treated with any other        medicaments like a NSAID, a DMARD, a TNFα inhibitor, an        Interleukin 6 inhibitor and/or an analgetic agent.

By means of administering a delayed-release tablet, the daily dose ofthe glucocorticoid may be substantially reduced compared to animmediate-release tablet of the glucocorticoid. Thus, thedisease-inhibiting effect may be obtained by a significantly lower doseof the active ingredient, whereby the occurrence and/or intensity ofsite effect is diminished. For example, the daily dose of theglucocorticoid can be reduced by at least 10%, more preferably by atleast 20%, e.g. by 10-50% compared to an immediate-release tablet. Thus,the reduced daily dose of prednis(ol)one in Prednisone delayed-releaseis preferably in the range of 1 to 5 mg/day compared to 6-10 mg/day fora standard IR tablet.

The treatment according to the present invention may comprise thetreatment of a rheumatic disease and/or osteoarthritis without anyfurther medicament. On the other hand, the invention may comprise thetreatment of a rheumatic disease and/or osteoarthritis in combinationwith at least one further medicament which is preferably selected fromthe groups of NSAIDs, DMARDs, TNF a inhibitors, IL-6 inhibitors,analgetic agents or combinations thereof. Especially preferred is acombination with Tarenflurbil.

NSAIDs are preferably selected from arylalkanoic acids (Diclofenac,Indometacin, Sulindac) from 2-arylpropionic acids (Carprofen,Fenoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Ketorolac, Laxoprofen,Naproxen, Tiaprofenic acid), from N-arylanthranilic acids (Mefenamicacid, Meclofenamic acid), from Oxicams (Piroxicam, Meloxicam) or fromCoxibs (Celecoxib, Parecoxib, Etoricoxib) or from combinations thereof.Especially preferred is a combination with Tarenflurbil.

DMARDs are preferably selected from gold preparations, chloroquine,azathioprine, sulfasalazine, cyclophosphamide, penicillamine,hydroxychloroquine, methotrexate, thorium dioxide suspension,levamisole, cyclosporin, interferone, leflunomide or from combinationsthereof.

TNF a inhibitors and IL 1 inhibitors are preferably selected fromantibodies or soluble receptors such as etanercept, inflixima, anakinra,adalimumab and from cominations thereof.

IL-6 inhibitors are preferably selected from antibodies or solublereceptors such as tocilizumab.

Analgetic agents are preferably selected from salicylates (Aspirin,Methyl salicylate, Diflunisal, Benorylate, Faislamine, Amoxiprin), frompyrazolidine derivatives (Phenylbutazone, Oxyphenylbutazone) orparacetamol or from combinations thereof.

The dose of the at least one further medicament may be substantiallyreduced e.g. by at least 10%, preferably by at least 20%, e.g. by10-50%. Alternatively, the first usage of TNF a inhibitors or IL-6inhibitors can be postponed to a later point in time.

The present invention particularly refers to the treatment of arheumatic disease selected from rheumatoid arthritis, ankylosatingspondylitis, polymyalgia rheumatica and/or to the treatment ofosteoarthritis. Based on the results of the clinical trials described inthe present application, it is evident that the delayed-release dosageform of a glucocorticoid, particularly a long-term treatment, is oftherapeutic benefit. Particularly in the case of osteoarthritis or arheumatic disease having an osteoarthritic component, the administrationof the delayed-release dosage form is effective without having undesiredside effects.

The dose of the glucocorticoid may vary during the course of treatment.For example, the patient may be administered a relatively high doseduring the initiation of therapy (e.g., about 10-40 mg/day or higher ofprednisone, or an equivalent amount of another glucocorticoid), whichmay be reduced downward over a period of time (e.g., over 3-4 weeks)according to the patient's response, to a maintenance therapy dose ofabout 10 mg/day or less of prednisone, or an equivalent amount ofanother glucocorticoid. Alternatively, the patient may be started on arelatively low dose, which may be adjusted upward over a period of time(e.g., over 3-4 weeks) to a maintenance therapy dose of about 10 mg/dayor less of prednisone, or an equivalent amount of anotherglucocorticoid.

Further, the present invention is described in more detail by thefollowing examples.

EXAMPLE

Clinical studies. The clinical development program supporting thepresent application for the delayed-release prednisone tablet“Prednisone delayed-release” comprised 3 phase I studies and 1 phase IIIstudy:

-   -   Phase I studies: These 3 randomized, open-label, crossover        studies on 69 healthy men investigated the comparative        bioavailability and pharmacokinetic characteristics of 6        experimental galenic delayed-release formulations each        containing 5 mg prednisone. The studies were performed to allow        selection of a delayed-release tablet with appropriate        characteristics for evening administration to RA patients (i.e.        a suitable lag time and high bioavailability that was not        affected by food). Single doses of each of the delayed-release        tablets were compared to a single dose of a reference immediate        release (IR) prednisone tablet (Decortin® 5 mg tablets marketed        by Merck KGaA).    -   Phase III study: In this randomized, parallel-group,        double-blind, double-dummy study on 288 adult RA patients, the        final prednisone delayed-release tablet formulation was        administered in the evening for 12 weeks. The daily prednisone        dose of 3 to 10 mg was achieved with 1 and 5 mg tablets.        Efficacy and safety were compared with the reference IR product        given in the morning.

This is a novel study design which was not used by Arvidson (1997) orKaratay (2002) as patients in these studies were corticoid naïve. Inthose studies the administration of a standard IR prednis(ol)one tabletat 2.00 and 8.00 was compared.

Study Design and Methodology

Study design. The studies were specifically designed to compare theefficacy and safety of Prednisone delayed-release given in the eveningwith standard IR prednisone (Decortin®, Merck KGaA) given in the morningat 08:00 over a period of 12 weeks. Prednisone delayed-release and thereference product both contained the same drug (prednisone) and differedsolely with respect to the timepoint at which this was released in thegastrointestinal tract. Timing of the evening dose (22:00±30 min) wasbased on results from a previous pharmacokinetic study with Prednisonedelayed-release which showed first detectable plasma concentrations ofprednisone and its active metabolite prednisolone after 4 hours andmaximal plasma concentrations about 6 h after administration. Thisspecific plasma profile with Cmax at 04:00 is expected to suppress theknown early morning increase of pro-inflammatory cytokines, and thusreduce morning stiffness.

Inclusion of a placebo arm was not considered necessary or ethical dueto the proven efficacy of prednisone. Blinding was essential in thisstudy to avoid bias. As the Prednisone delayed-release tablets andreference product tablets differed in appearance a double-dummytechnique was used to maintain the treatment blind.

The study had a 1- to 2-week screening period that was followed by a12-week double-blind treatment period with visits after 2 and 6 weeks.This 12-week period was considered to be sufficiently long todemonstrate any differences in the primary and secondary efficacyendpoints (see below). At the end of the 12-week double blind period,patients who completed the 12-week double-blind period were offered tocontinue in an open-label 9-month follow up period, during which allpatients received active treatment with Prednisone delayed-release.

Prednisone dose. Patients were to continue on the same stable low doseof prednisone (or equivalent) that they received in the month beforeentering the study. During the study prednisone doses of 3 to 10 mg/daywere achieved with appropriate combinations of Prednisonedelayed-release or IR tablets containing 1 and 5 mg prednisone; dailydoses of 2.5 and 7.5 mg prednisone were rounded to 3 and 8 mg,respectively. A constant low prednisone dose was given throughout thetreatment phase to ensure that any differences between the treatmentgroups were not due to dose changes.

Primary objective and efficacy endpoint. The primary objective of thestudy was to show whether administration of the new delayed-releaseformulation of prednisone (i.e. Prednisone delayed-release) in theevening was superior to the standard morning administration ofimmediate-release (IR) prednisone in reducing the duration of morningstiffness. The patient diary card was appropriately designed to capturerelevant clock times in minutes: wake-up, morning medication intake,resolution of morning stiffness. The primary variable was “the relativechange in duration of morning stiffness from baseline at individualstudy end in the double-blind treatment phase”, whereby the duration ofmorning stiffness was the difference between the time of resolution ofmorning stiffness and the time of awakening. Morning stiffness waschosen as the primary variable because it was expected to be directlyaffected by inhibition of night-time IL-6 peaks after delayed release ofprednisone.

Secondary efficacy endpoints. In addition to morning stiffness, thestudy included a comprehensive battery of supportive secondary endpointsthat were based on regulatory recommendations (CPMP/EWP/556/95 rev 1).Patients assessed their quality of sleep, pain intensity (VAS), andglobal disease activity (VAS). They also documented their use ofanalgesics and completed validated questionnaires on their health status(HAQ) and quality of life (SF36). Investigators counted the numbers ofswollen and tender joints (28 joints) and assessed global diseaseactivity (5-point scale). Laboratory variables (ESR, CRP, IL-6) wereassessed from blood samples taken as early as possible in the morning toinvestigate the inflammatory state of the disease. Osteocalcin was alsomeasured as an indicator of bone metabolism.

Two validated composite variables were used: the disease activity score(DAS 28) and the ACR20 responder rate. The DAS 28 was computed from thejoint scores, the ESR and the patient's global assessment of diseaseactivity. An ACR responder was defined as a patient with improvement ofat least 20% of the baseline values in the tender joint count, swollenjoint count and at least 3 of the following 5 variables: pain intensity,investigator global assessment, patient global assessment, HAQdisability index, or ESR.

Inclusion criteria were designed to enroll adult patients (18 to 80years) with active RA who were typical of the general RA populationbeing treated with a combination of stable corticoid medication andDMARDs. Patients had to have a documented history of RA and present withactive symptoms of disease, i.e. morning stiffness of 45 min, pain ≧30mm (VAS), ≧3 painful joints, ≧1 swollen joints and elevated ESR and/orCRP.

Patients had to have been treated with the following state-of-the-art RAmedications for at least 3 months before entering the study:

-   -   DMARDs (unless they were not tolerated)    -   Prednis(ol)one, with a low, stable dose of 2.5 to 10 mg        prednisone (or equivalent) for at least 1 month prior to        screening

Patients were to continue on their RA medications at the same dosethroughout the 12-week double-blind treatment phase. These restrictionsare considered appropriate because they ensure that any differencesbetween the treatment groups were due to the different dosing modalitiesof prednisone not to dose changes in the corticoid or concomitantDMARDs.

Study Results

288 randomized patients were treated in total, 144 patients withPrednisone delayed-release and 144 with the IR reference product. Thebaseline characteristics of the two treatment groups were comparable(mean values for the overall population): age (55 years), gender (85%female), morning stiffness (173 min), disease duration (115 months), DAS28 (5.9), daily dose of prednis(ol)one (6.6 mg), medications prior toscreening (DMARDs 94%, non-steroidal anti-inflammatory drugs [NSAIDs]80% patients). Also the medical history of the patients in bothtreatments are comparable. Table 1 summarizes the Diseasecharacteristics. Patients with different disease duration (short,mid-term and long-lasting) and different disease activity (DAS: mild,moderate and severe) were included. TABLE 1 Disease characteristics atbaseline (ITT population) Prednisone Standard IR Disease characteristicsdelayed-release prednisone Total at baseline (N = 144) (N = 144) (N =288) RA No. of subjects n (%) 144 (100.0) 144 (100.0) 288 (100.0) MeanDuration Months 115.1  115.4  115.3  Duration <2 years, n (%) 19 (13.2)18 (12.5) 37 (12.8) 2-5 years, n (%) 37 (25.7) 37 (25.7) 74 (25.7) 5-10years, n (%) 33 (22.9) 31 (21.5) 64 (22.2) >10 years, n (%) 55 (38.2) 58(40.3) 113 (39.2)  Pre-treatment (yes) 144 (100.0) 144 (100.0) 288(100.0) Stable dose [mg] Mean 6.5 6.7 6.6 of prednis(ol)one DAS28 Mean5.8 5.9 5.9 SD 0.8 0.9 0.8 Range 3.3-8.1 3.7-7.7 3.3-8.1 DiseaseAsymptomatic 0 (0.0) 0 (0.0) 0 (0.0) activity Mild 13 (9.0)  14 (9.7) 27 (9.4)  (physician's Moderate 103 (71.5)  102 (70.8)  205 (71.2) assessment) Severe 28 (19.4) 28 (19.4) 56 (19.4) [n (%)] Very severe 0(0.0) 0 (0.0) 0 (0.0) Pain intensity mean 57.9  59.7  58.8  (HAQ-VAS)[mm] SD 14.8  15.8  15.3  Range 18-95 25-96 18-96 HAQ-DI score mean 1.51.5 1.5 SD 0.6 0.5 0.5 Range 0.0-2.9 0.0-2.8 0.0-2.9

Efficacy Results

Primary efficacy variable and morning stiffness. As planned, the primaryefficacy analysis in the study was performed on the intention-to-treatpopulation (i.e. all randomized patients as randomized) using “lastobservation carried forward” methodology. TABLE 2 Duration of morningstiffness after 12 weeks of treatment (intention-to-treat population)Duration of morning Prednisone delayed- Prednisone Standard stiffness(mean (SD)) release (N = 144) (N = 144) Baseline [min] 164.1 (101.4)182.5 (125.0) (N = 125) (N = 129) At Week 12 (Final week) 120.9 (140.5)157.4 (145.6) [min] (N = 127) (N = 131) Relative change [%] −22.66(89.1)  −0.39 (89.0)  (N = 125) (N = 129) Treatment difference LS mean(SD) [%] 22.4 (11.1) Lower limit of 95% Cl 0.493 p-value 0.0226(one-sided)

The primary variable was “the relative change in duration of morningstiffness from baseline at individual study end in the double-blindtreatment phase”, whereby the duration of morning stiffness was thedifference between the time of resolution of morning stiffness and thetime of awakening. The reduction in duration of morning stiffness underPrednisone delayed-release treatment was higher than under standard IRprednisone throughout the 12-week treatment period.

At the end of the first week of treatment there was a difference of 10%between the two treatment groups. The relative reduction betweenbaseline and final week of treatment was 22.7% in the Prednisonedelayed-release group and 0.4% in the standard prednisone group. Thus,Prednisone delayed-release was shown to be superior to standardprednisone IR tablet in a statistically significant manner (p<0.025, onesided) and the primary study objective was met.

A difference between the two groups is obvious from the first week on,however the longer the treatment the more pronounced are the differencesin favour for Prednisone delayed-release. This is illustrated in Table 3and FIG. 1: TABLE 3 Mean daily duration of morning stiffness per week(intention-to-treat population) Mean daily duration of morning stiffnessPrednisone per week (mean delayed-release Prednisone Standard (SD)) (N =144) (N = 144) Baseline [min] 164.1 (101.4) (N = 125) 182.5 (125.0) (N =129) At Week 1 [min] 159.4 (127.3) (N = 126) 186.4 (135.6) (N = 131)Relative change [%] −1.4 (62.4) (N = 124) 9.3 (60.2) (N = 129) At Week 2[min] 144.9 (136.4) (N = 123) 187.7 (154.4) (N = 131) Relative change[%] −12.5 (70.0) (N = 121) 8.1 (71.6) (N = 129) At Week 3 [min] 138.3(137.1) (N = 122) 164.2 (137.2) (N = 127) Relative change [%] −13.8(73.9) (N = 120) 0.3 (63.6) (N = 125) At Week 4 [min] 129.5 (128.3) (N =117) 163.7 (124.2) (N = 123) Relative change [%] −23.3 (54.7) (N = 115)3.5 (72.5) (N = 121) At Week 5 [min] 126.0 (126.9) (N = 117) 159.7(128.5) (N = 121) Relative change [%] −25.9 (55.1) (N = 115) 6.0 (85.1)(N = 119) At Week 6 [min] 117.9 (128.2) (N = 112) 154.2 (123.7) (N =119) Relative change [%] −28.3 (59.8) (N = 110) 5.3 (82.5) (N = 117) AtWeek 7 [min] 109.0 (113.9) (N = 109) 156.5 (144.9) (N = 119) Relativechange [%] −33.5 (49.1) (N = 107) −2.6 (74.2) (N = 117) At Week 8 [min]98.7 (93.8) (N = 105) 152.1 (125.3) (N = 116) Relative change [%] −37.1(45.8) (N = 103) −5.2 (62.5) (N = 114) At Week 9 [min] 90.7 (87.5) (N =107) 146.4 (123.1) (N = 116) Relative change [%] −41.3 (46.5) (N = 105)−5.6 (68.8) (N = 115) At Week 10 [min] 92.7 (90.8) (N = 105) 147.9(134.1) (N = 117) Relative change [%] −40.5 (46.9) (N = 103) −5.0 (83.0)(N = 116) At Week 11 [min] 95.9 (97.2) (N = 103) 148.9 (136.4) (N = 116)Relative change [%] −37.7 (50.1) (N = 101) −1.2 (95.8) (N = 115) At Week12 [min] 98.1 (100.5) (N = 102) 149.5 (134.8) (N = 111) Relative change[%] −33.1 (75.4) (N = 100) −3.4 (92.1) (N = 111)

The weekly assessment of the mean daily duration of morning stiffnessrevealed that the decrease and thus the improvement begins already after2 weeks of treatment in the Prednisone delayed-release group. The meandaily duration of morning stiffness continues to decrease steadilythereafter, whereas in the prednisone standard group, there was no cleartendency for the changes during the 12-week treatment.

This result is surprising as Karatay showed in 2002 that such an effectsbe expected.

Due to the superiority of Prednisone delayed-release against standardPrednisone of a reduction in the daily dose of e.g. 25-30% could bepossible under

In the Phase III trial the superiority of a very low dose of Prednisonein the new delayed-release tablet compared to standard IR prednisonecould be shown supporting the proposed dose reduction.

Table 4 shows the frequencies of starting stable doses of prednisone inthe Prednisone delayed-release and standard prednisone groups of theintention-to-treat (ITT) population. The frequency profiles in bothtreatment groups were similar, with the most common dose being 5 mg (50%subjects), followed by 7 and 10 mg (approximately 20% each). TABLE 4Frequencies of stable doses of prednisone at start of study (ITTpopulation) Number (%) subjects Stable Prednisone Standard prednisonedose delayed-release prednisone (mg) (N = 144) (N = 144) 2 1 (0.7) 0 (—)3 8 (5.6) 2 (1.4) 4 1 (0.7) 1 (0.7) 5 72 (50.0) 73 (50.7) 6 1 (0.7) 0(—) 7 28 (19.4) 30 (20.8) 8 4 (2.8) 3 (2.1) 9 0 (—) 0 (—) 10 29 (20.1)35 (24.3)

The median value of the mean daily prednisone dose across all subjectsin the ITT population was 5.18 mg. Subgroup analyses were performed onthe primary efficacy variable (i.e. the relative change from baseline induration of morning stiffness) in subjects with a mean daily prednisonedose ≦5.18 mg and >5.18 mg.

In order to investigate the comparability of subgroups, selecteddemographic and baseline characteristics were analyzed: age, gender,ethnic origin, body weight, body height, duration of RA, HAQ-DI, painintensity (VAS), SF36, and DAS28. Comments on age, duration of RA, andDAS28 as the most clinically relevant parameters are included below.There were no clinically relevant imbalances between subgroups in theother baseline variables.

Descriptive statistics for baseline demographics and the primaryefficacy variable are presented for mean daily prednisone doses of >5.18mg and ≦5.18 mg in each of the treatment groups of the ITT population inTable 5. The difference for the primary efficacy variable between thetreatment groups is also given (as calculated by ANOVA, model A). TABLE5 Baseline demographic variables and primary efficacy variable insubjects with a mean daily prednisone dose <5.18 mg or >5.18 mg* (ITTpopulation) Prednisone delayed-release Standard prednisone (N = 144) (N= 144) Variable/subgroup N Mean (SD) n Mean (SD) Baseline demographicvariables Age, years Mean daily dose ≦5.18 mg* 78 55.1 (10.5) 65 54.6(11.9) Mean daily dose >5.18 mg* 65 54.3 (12.0) 77 56.1 (10.9) Durationof RA, months Mean daily dose ≦5.18 mg* 77 115.5 (98.4) 65 113.0 (111.4)Mean daily dose >5.18 mg* 65 116.3 (86.8) 77 117.1 (75.1) DAS28 scoreMean daily dose ≦5.18 mg* 78 5.8 (0.8) 64 5.8 (0.9) Mean dailydose >5.18 mg* 65 5.8 (0.7) 76 6.0 (0.8) Duration of morning stiffnessMean daily dose ≦5.18 mg* Baseline, min 67 163.54 (109.92) 59 174.79(132.47) Final week, min 69 119.25 (132.40) 60 169.36 (174.47) Relativechange from 67 −26.93 (67.72) 59 7.88 (106.38) baseline to final week, %Difference between groups LS mean (SE), % 34.98 (15.57) 95% Cl 4.13,65.83 p-value 0.0134 (one-sided) Mean daily dose >5.18 mg* Baseline, min57 164.81 (92.36) 68 189.74 (120.43) Final week, min 57 122.81 (152.12)69 144.22 (113.49) Relative change from 57 −17.64 (110.12) 68 −8.76(70.83) baseline to final week, % Difference between groups LS mean(SE), % 15.45 (16.14) 95% Cl −16.54, 47.45  p-value 0.1702 (one-sided)*5.18 mg is the median value of the mean daily prednisone dose acrossall subjects in the ITT population.LS = least square, SE = standard error

There were no differences in mean age, mean duration of RA, or meanDAS28 score between subjects receiving a mean daily prednisone dose of≦5.18 mg and those receiving a mean daily dose of >5.18 mg in either ofthe 2 treatment groups.

In the Prednisone delayed-release group, morning stiffness decreased inboth dose subgroups, with a larger decrease in subjects with a meandaily prednisone dose ≦5.18 mg than in subjects with a daily dose >5.18mg.

In the standard prednisone group, subjects with a mean daily dose ≦5.18mg showed an increase in the duration of morning stiffness. In subjectswith a mean daily dose >5.18 mg, morning stiffness decreased but thedecrease was not as large as in either of the Prednisone delayed-releasedose subgroups.

Recurrence of Stiffness During the Day

In about 58% of the subjects in both treatment groups, recurrence ofstiffness during the day was reported at baseline. After two weeks oftreatment, the percentage was slightly lower in both treatment groups;after six weeks of treatment, the percentages were notably lower in bothtreatment groups with no major difference between the treatments; after12 weeks of treatment, the percentage of subjects concerned was againnotably lower compared to the 6-week value in both treatment groups.

Secondary Efficacy Variables. TABLE 6 Intensity of pain (VAS) after 12weeks of treatment (intention-to-treat population) Prednisone Intensityof pain (VAS) delayed-release Prednisone Standard (mean (SD)) (N = 144)(N = 144) Baseline [mm] 50.9 (15.2) 52.3 (17.2) (N = 141) (N = 143) AtWeek 12 (Final week) 45.7 (24.1) 45.1 (23.1) [mm] (N = 142) (N = 144)Relative change [%] −8.57 (55.0)  −6.53 (83.9)  (N = 141) (N = 143)

According to the relative changes, the intensity of pain (VAS) wasimproved after 12 weeks of treatment by both treatments. In the ITT set,the treatment difference in the relative change in intensity of pain(VAS) was calculated to be 4.91% (SD 8.08%). A difference between the 2groups in favour of Prednisone delayed-release has been observed, whichwas much more pronounced in the per-protocol set (−19% for Prednisonedelayed-release vs-5% for Prednisone standard). The mean number of dayswith analgesics per week did not change notably after treatment start inboth treatment groups. There is no difference between the two treatmentgroups after 2, 6, and 12 weeks of treatment. However, as underPrednisone delayed-release the intensity of pain went down it can beassumed that in patients with early RA or under long-term treatment alsoa reduction of painkillers will be seen. No differences were observed inall other efficacy variables as listed in the following.

Quality of Sleep

The mean daily quality of sleep (VAS) did not improve in both treatmentgroups. There were no marked differences between baseline of the twotreatment groups and the means of absolute changes after 2, 6, and 12weeks of treatment.

Disease Activity Score (DAS 28)

The Disease Activity Score (DAS 28) decreased in both treatment groups.After two weeks of treatment, the decreases were small, whereas aftersix and 12 weeks of treatment the decreases were more pronounced.Absolute and relative changes were similar between the two treatmentgroups after 2, 6, and 12 weeks of treatment.

Tender and Swollen Joint Count

The tender and swollen joint count decreased in both treatment groups.After two weeks of treatment, the decreases were notable and furtherdecreases were observed in both treatment groups after six and 12 weeksof treatment.

Subject's Global Assessment of Disease Activity

The mean subject's global assessment of disease activity (VAS) decreasedin both treatment groups after start of the treatment with no relevantdifferences between timepoints and treatments.

Health Assessment Questionnaire Disability Index (HAQ-DI) and Quality ofLife (SF36)

The HAQ-D1 and SF36 scores were similar in both treatment groups atbaseline as well as after 12 weeks of treatment.

Physician's Global Assessment of Disease Activity

In both treatment groups, the number and percentage of subjects whosedisease activity was assessed by the physician as mild increased duringthe course of the treatment; the number and percentage of subjects whosedisease activity was assessed by the physician as severe decreased.

Inflammatory Signs

The mean values of the inflammatory signs CRP and IL-6 at baseline aswell as after 2, 6 and 12 weeks of treatment and the respective relativechanges are presented in Table 7. TABLE 7 Inflammatory signs (CRP, IL-6)(intention-to-treat population) Inflammatory signs Prednisone (median(min, max)) delayed-release Prednisone Standard CRP [mg/L] Baseline(Visit 2) 9.9 (1.0, 105.1) 12.2 (1.0, 177.5) At Week 2 (Visit 3) 10.2(1.0, 159.0) 11.2 (1.0, 106.3) Relative change [%] 13.0 (−96.1, 543.2)0.0 (−93.1, 1535.4) At Week 6 (Visit 4) 9.9 (1.0, 90.3) 10.7 (1.0,152.5) Relative change [%] 8.0 (−93.4, 695.2) 0.0 (−94.2, 2377.8) AtWeek 12 (Visit 5*) 9.1 (1.0, 185.0) 11.5 (1.0, 145.3) Relative change[%] 2.4 (−98.2, 1419.6) 0.0 (−93.0, 2605.6) IL-6 [IU/L] Baseline(Visit 1) 860 (200, 23000) 1110 (200, 20800) At Week 12 (Visit 5*) 470(200, 9530) 1080 (200, 22700) Absolute change −160 (−13460, 9080) 0.0(−16190, 18100) Relative change [%] −28.6 (−96.8, 2018) 0.0 (−98.1,3017)

The median CRP values did not change notably during the 12-weektreatment in both treatment groups.

IL-6 values decreased during the 12-week treatment in the Prednisonedelayed-release treatment group, but remained unchanged in theprednisone standard treatment group. Median values seem to have beenhalved by the Prednisone delayed-release preparation and the overallrange was much smaller after 12 weeks of treatment. The variability wasvery high in both groups. However, the change under Prednisonedelayed-release from baseline to 12 weeks was significantly lower(p<0.001). Also, there was a statistically significant differencebetween the two treatment groups after 12 weeks.

Osteocalcin

Osteocalcin is a sensitive measure to the bone metabolism (Heshmati1998). The mean osteocalcin values at baseline (screening) as well asafter 12 weeks of treatment and the respective relative changes arepresented in Table 8. TABLE 8 Osteocalcin (intention-to-treatpopulation) Osteocalcin [ng/mL] Prednisone (mean (SD)) delayed-releasePrednisone Standard Baseline (Visit 1) 20.95 (11.31) 20.04 (9.95) AtWeek 12 (Visit 5*) 20.40 (12.82) 19.43 (9.49) Relative change [%] -1.7(33.0)  3.9 (46.4)

There were no differences between baseline and endpoints or between thetwo treatments. Thus, it can be concluded that night-time administrationof low dose prednisone does not have a negative impact on bonemetabolism and risk of osteoporosis.

Continued Efficacy Over During 9 Month Open Follow Up

Out of 288 patients enrolled into the double blind treatment period, atotal of 249 subjects entered the open follow-up phase of the study, 219subjects completed this phase (see Table 9). TABLE 9 Disposition ofSubjects Number of subjects Criterion n (%) Enrolled into double-blindphase 288 Enrolled in open follow-up 249 (100)  Withdrawn  30 (12.0*)Who completed open follow-up 219 (88.0*)

Although efficacy was not the main objective of this open follow-upstudy, the order of reporting was kept the same as in the previous studyreport on the double-blind phase. In the open follow-up phase theinterpretation of the efficacy data was focused on the following threeaspects:

-   -   maintenance of the effects on stiffness duration achieved by        prednisone delayed-release during the double-blind phase in the        former prednisone delayed-release group    -   reduction of morning stiffness to the same extent in the        subjects of the former prednisone standard group after three        months of treatment with prednisone delayed-release at Visit 6    -   further reduction of morning stiffness in the study population        after Visit 6 up to 9 months (Visit 8) or after 12 months of        treatment with prednisone delayed-release, respectively.        Mean Daily Duration of Morning Stiffness

The mean daily duration of morning stiffness at start of thedouble-blind period (Visit 2), at start of the open follow-up period(Visit 5) and at end of study (Visit 8) as well as the relative changesare presented in Table 10 and FIG. 2 for the study population. TABLE 10Mean Daily Duration of Morning Stiffness at Month 9 of Follow-Up (Visit8) Number of subjects Prednisone Prednisone delayed-release StandardTotal (N = 120) (N = 129) (N = 249) mean (SD) mean (SD) mean (SD) medianmedian median Duration of morning stiffness [min] (min; max) (min; max.)(min; max) Visit 2 (Start of Double−blind Period) 156.27 (97.25) 182.40(127.43) 169.80 (114.38) 137.14 149.29 143.21 (41.43; 659.29) (32.14;720.0)  (32.14; 720.0) (n = 107) (n = 115) (n = 222) Visit 5 (Start ofFollow−up Period)  98.20 (100.22) 150.31 (139.48) 125.56 (124.92)  75.36116.07  83.93  (0.0; 470.0) (0.0; 720.0)  (0.0; 720.0) (n = 114) (n =126) (n = 240) Relative change [%] to Visit 2 −34.47 (68.99) −1.44(93.07) −17.10 (83.99)  −37.29 −19.05 −28.75 (−100.00; 433.53) (−100.00; 609.86)   (−100.00; 609.86)  (n = 101) (n = 112) (n = 213)Visit 8* (Month 9 of Follow−up)  73.43 (92.32)  92.88 (124.59)  83.63(110.60)  42.14 60.0  46.43  (0.0; 502.5) (0.0; 720.0)  (0.0; 720.0) (n= 97)  (n = 107) (n = 204) Relative change [%] to Visit 2 −55.07 (44.79)−44.90 (63.73)  −49.71 (55.67)  −63.13 −62.96 −63.02 (−100; 133.33)(−100; 269.44)   (−100; 269.44) (n = 87)  (n = 97)  (n = 184) Relativechange [%] to Visit 5  −7.81 (144.62) −13.90 (146.98) −11.22 (145.56)−38.33 −40.70 −40.70 (−100; 783.75) (−100; 950)   (−100; 950)  (n = 78) (n = 99)  (n = 177)*Incl. premature termination

Starting treatment with prednisone delayed-release with longer stiffnessduration at Visit 5, the former prednisone standard group achievedalmost identical reduction, when percent relative change is calculatedfrom Visit 8 to Visit 5 or from Visit 8 to Visit 2. For all subjects ofthe study population in the follow-up phase, a further mean reduction of11.22% (Visit 8 compared to Visit 5) was gained. The total reduction ofstiffness duration by 49.71% was observed on long term treatment betweenVisit 2 and 8.

Mean Daily Duration of Morning Stiffness after Start of Treatment withPrednisone Delayed-Release (Visit 2/Visit 5)

The mean daily duration of morning stiffness at start of thedouble-blind period (Visit 2) as well as at start of the follow-upperiod (Visit 5) and after 3, 6, 9, and 12 months (3-month intervals) ofprednisone delayed-release treatment including respective relativechanges are presented in Table 11. TABLE 11 Mean Daily Duration ofMorning Stiffness after Start of Treatment with Prednisonedelayed-release (Visit 2/Visit 5) Number of subjects PrednisonePrednisone delayed-release Standard Total Mean daily duration of morning(N = 249) (N = 249) (N = 249) stiffness mean (SD) mean (SD) mean (SD)Visit 2 (Start of Double-blind Period) [min] 156.27 (97.25) — 153.04(121.71)   (n = 107) (n = 233) Visit 5 (Start of Follow-up Period) [min]150.31 (139.48) (n = 126) after 3 months of Prednisone delayed-  98.20(100.22)  85.17 (112.45) 91.92 (106.25) release treatment [min]  (n =114) (n = 106) (n = 220) Relative change [%] −34.47 (68.99) −46.06(46.86)  −40.18 (59.27)   (n = 101) (n = 98)  (n = 199) after 6 monthsof Prednisone delayed-  65.70 (100.95)  81.08 (104.79) 74.08 (103.10)release treatment [min] (n = 96) (n = 115) (n = 211) Relative change [%]−56.06 (54.20) −32.83 (116.64) −43.13 (94.71)  (n = 86) (n = 108) (n =194) after 9 months of Prednisone delayed-  62.43 (87.49)  92.88(124.59) 78.10 (108.99) release treatment* [min]  (n = 101) (n = 107)(208) Relative change [%] −61.35 (45.67) −13.90 (146.98) −36.23(113.67)  (n = 88) (n = 99)  (n = 187 after 12 months of Prednisonedelayed-  73.43 (92.32) — release treatment* [min] (n = 97) Relativechange [%] −55.07 (44.79) (n = 87)Relative changes refer to values given in bold case*Incl. premature termination

In Table 11 the duration of morning stiffness is presented as treatmentduration of prednisone delayed-release independent from Visits. Relativechanges were calculated from the data at Visit 2 for the formerprednisone delayed-release group and from the data of Visit 5 for theformer prednisone standard group. Taking advantage of the higher numberof available data, the interpretation of the results was carried out forthe total numbers.

Before starting with the treatment of prednisone delayed-release themean daily duration of morning stiffness was 153 min. After three monthsof treatment stiffness duration was reduced to a mean of 92 min andafter six months further to 74 min. After nine months of prednisonedelayed-release treatment mean daily duration of morning stiffness was78 min. For the subjects of the former prednisone delayed-release groupdata were also available after 12 months of prednisone delayed-releasetreatment. For these subjects stiffness duration was similar to thoseafter six and nine months of treatment (73 min). No weaning of effectswas observed. Thus, the mean duration of morning stiffness was reducedto the half after six months of prednisone delayed-release treatment.

Inflammatory Signs

The median values of the inflammatory signs CRP and IL-6 during the openfollow-up period (Visit 5 to Visit 8) and the respective absolutechanges are presented in Table 12 and FIG. 3. TABLE 12 InflammatorySigns (CRP, IL-6) Number of subjects Prednisone delayed- releasePrednisone Standard Total (N = 120) (N = 129) (N = 249) Inflammatorysigns median (min; max) median (min; max) median (min; max) CRP* [mg/L]Visit 5 (Start of Follow-up) 8.60 (n = 120) 10.90 (n = 129) 9.40 (n =249)  (1.00; 139.80)  (1.00; 145.30) (1.00; 145.30) Visit 6 (Month 3 ofFollow-up) 8.55 (n = 108)  8.15 (n = 118) 8.35 (n = 226) (1.00; 81.40) (1.00; 152.40) (1.00; 152.40) Absolute change −0.45 (n = 108)  −1.20 (n= 118) −0.70 (n = 226)  (−131.20; 77.70)   (−123.20; 95.00)   −131.20;95.00)   Visit 7 (Month 6 of Follow-up) 7.00 (n = 109)  9.05 (n = 118)8.00 (n = 227) (1.00; 71.00) (1.00; 69.70) (1.00; 71.00)  Absolutechange −0.60 (n = 109)  −0.95 (n = 118) −0.80 (n = 227)  (−122.60;49.00)   (−108.10; 25.80)   (−122.60; 49.00)   Visit 8*** (Month 9 ofFollow-up) 8.40 (n = 112)  8.35 (n = 124) 8.35 (n = 236) (1.00; 83.30)(1.00; 86.50) (1.00; 86.50)  Absolute change −0.25 (n = 112)  −0.25 (n =124) −0.25 (n = 236)  (−129.10; 68.30)   (−76.90; 68.70)  (−129.10;68.70)   IL-6** [IU/L] Visit 5 (Start of Follow-up)  460 (n = 120)  1050(n = 127) −710 (n = 247) (200; 9530)  (200; 22700) (200; 22700) Visit8*** (Month 9 of Follow-up)  510 (n = 111)   570 (n = 123) −525 (n =234)  (200; 18300) (200; 8100) (200; 18300) Absolute change   0 (n =111)   −300 (n = 121) − 45 (n = 232) (−6830; 16110)  (−20600; 6270)  (−20600; 16110)  *Values <1.0 mg/L were set to 1.0 for analysis**Values <200 IU/L were set to 200 for analysis***Incl. premature termination.

The median CRP values did not change notably during the nine months ofopen follow-up treatment with prednisone delayed-release, except in theformer prednisone standard group at Visit 6 where the CRP value wasdecreased most compared to Visit 5.

As the variability of the IL-6 values was high in both groups, themedian was chosen for comparison rather than the mean values. IL-6values decreased notably in the former prednisone standard group from1050 IU/L to 570 IU/L. Thus, IL-6 concentrations were halved in thesubjects of the former standard group. This decrease of IL-6 was similarto the decrease of IL-6 in the prednisone delayed-release groupdescribed in the double-blind phase. No further reduction was observedin the subjects of the former prednisone delayed-release group.

Overview of Safety

The safety profile of glucocorticoids in the treatment of rheumatoidarthritis (RA) is well established). The main side effects consist ofosteoporosis leading to fractures, gastrointestinal disorders,cardiovascular disorders, increased risk of infections, hyperglycemia,suppression of the HPA axis, and opthalmologic disorders. It is acceptedthat many of these side effects are observed at high or medium doses butnot at low doses (Bijlsma et al. 2003, Bijlsma et al. 2005, Boers 2004,Buttgereit et al 2005, Conn 2001, Da Silva et al. 2005, Saag et al.1994).

Prednisone delayed-release is intended for the treatment of RA at lowdoses (3 to 10 mg prednisone/day) and contains the same active drugingredient as standard low-dose IR products. Prednisone delayed-releasediffers from standard products solely with respect to the recommendedtime of administration and timepoint of drug release within thegastrointestinal tract. The safety profile of low-dose prednisone iswell established and reflected in labeling for standard IR products.Clinically significant differences are not expected.

Brief Summary of Adverse Events in Phase III Trial Under PrednisoneDelayed-Release

In this study, 59 (41.0%) subjects of the Prednisone delayed-releasetreatment group and 59 (41.0%) subjects of the prednisone standardtreatment group experienced at least one treatment-emergent AdverseEvent (AE). A total of 35 subjects (12.2%) experienced AEs that wereconsidered by the investigator to be related to prednisone. AEs causingdiscontinuation of prednisone were experienced by 22 subjects (7.6%).

One subject receiving prednisone standard died on study within 18 daysafter first dose of prednisone. Seven subjects (2.4%) experienced SAEs,and in one subject of these 7 subjects, the SAE was judged to be relatedto prednisone by the investigator.

Table 13 summarizes the number of subjects experiencing AEs by type ofAE (MedDRA Preferred Term, in at least 1.0% of the treated group). TABLE13 Most common AEs and drug-related AEs in study 003 No. (%) subjectswith AE Prednisone Standard delayed-release prednisone Total Preferredterm (N = 144) (N = 144) (N = 288) All Aes 59 (41.0) 59 (41.0) 118(41.0) Rheumatoid arthritis 11 (7.6)  13 (9.0)  24 (8.3) Abdominal pain5 (3.5) 8 (5.6) 13 (4.5) upper Nasopharyngitis 4 (2.8) 8 (5.6) 12 (4.2)Headache 6 (4.2) 4 (2.8) 10 (3.5) Flushing 4 (2.8) 6 (4.2) 10 (3.5)Nausea 5 (3.5) 4 (2.8)  9 (3.1) Drug-related AEs 19 (13.2) 16 (11.1)  35(12.2) Abdominal pain 3 (2.1) 4 (2.8)  7 (2.4) upper Nausea 3 (2.1) 3(2.1)  6 (2.1) Headache 4 (2.8) 2 (1.4)  6 (2.1) Rheumatoid arthritis 1(0.7) 4 (2.8)  5 (1.7)

The most frequently reported AEs (frequency >1.0% of the subjects of thesafety set) by MedDRA Preferred Term were rheumatoid arthritis includingseveral terms for worsening (deterioration, escalation, exacerbation,flare etc.) (24 subjects, 8.3%), abdominal pain upper (13 subjects,4.5%) and nasopharyngitis (12 subjects, 4.2%). The incidences of theseAEs were similar in treatment groups.

During the 9 month open follow-up period, 127 subjects (51.0%)experienced at least one treatment-emergent adverse event (AE). A totalof 27 subjects (10.8%) experienced AEs that were by the investigator tobe related to prednisone delayed-release. AEs causing discontinuation ofprednisone delayed-release were experienced by 13 subjects (5.2%); 68subjects (27.3%) had AEs not known to be recovered at the end of thestudy.

Table 14 summarizes the most common AEs by type of AE (MedDRA PreferredTerm, in more than 2% of the subjects). TABLE 14 Most Common AdverseEvents (Frequency >1.0% Overall) Total (N = 249) Adverse Event(preferred term) n (%) Rheumatoid arthritis 36 (14.5) Flushing 13 (5.2) Upper respiratory tract infection 7 (2.8) Weight increased 7 (2.8) Backpain 7 (2.8) Bronchitis 6 (2.4) Hypercholesterolemia 6 (2.4) Arthralgia6 (2.4) Nasopharyngitis 6 (2.4) Feeling hot 5 (2.0)

The most frequently reported AEs (MedDRA Preferred Term) were rheumatoidarthritis (36 subjects, 14.5%) and flushing (13 subjects, 5.2%).Flushing was only reported by the subjects who participated in the CRHtesting. Upper respiratory tract infection, increased weight, or backpain were reported less frequently (seven subjects (2.8%) in each case).

Benefits and Risks Conclusions

Prednisone delayed-release is a novel, delayed-release tablet that hasbeen developed to optimize the efficacy of orally administered low-doseprednisone in the treatment of RA. Prednisone delayed-release has shownimproved efficacy compared to standard prednisone in patients with RAwithout increasing their prednisone dose. This improvement has beensolely obtained as a result of Prednisone delayed-release's uniquerelease characteristics. The safety profiles of Prednisonedelayed-release and standard prednisone were comparable and the patientswere thus not exposed to an increased risk.

The benefits and main features of Prednisone delayed-release can besummarized as follows:

A significant reduction of morning stiffness was obtained in patientswith long-standing RA who were pretreated with prednisone and DMARDs. Adecrease of 10% compared to baseline was already apparent at week 2 oftreatment. Under continued treatment this reduction increased inmagnitude and plateaued at about 30% to 40% from week 7 onwards. In 50%of the patients (median values), the duration of morning stiffness wasreduced by at least one third (33.9%) during the double blind treatmentphase. At the end of the 9 month open label follow-up period, a decreasein the duration of morning stiffness of 49% compared to baseline wasobserved (mean baseline duration of morning stiffness was 3 hours).Morning stiffness is one of the most distressing symptoms for RApatients and thus the observed sustained reduction for at least 12months under Prednisone delayed-release can be considered a clinicallymeaningful improvement.

Both in the double blind and the 9 month open follow-up period, thereduction in morning stiffness was accompanied by a sustained paralleldecrease in the pro-inflammatory cytokine IL-6, thus confirming theproposed pharmacological rationale for adapting the timing of prednisoneadministration to the circadian rhythm of RA.

These results are surprising because it could not be expected fromformer investigations (Karatay 2002). Also the long lasting effect ofprednisone delayed-release over 12 months on reducing IL-6 levels isunexpected. Further, the long term correlation of IL-6 reduction andmorning stiffness reduction could not be expected from formerinvestigations.

Maximum plasma levels of prednisone in the early morning hours areobtained by administration of Prednisone delayed-release at about 22:00which is an acceptable time for the patient.

Prednisone delayed-release tablets can be used in patients with severe,moderate or mild disease.

Prednisone delayed-release tablets can be used in patients with short,mid-term or long-lasting disease duration.

Prednisone delayed-release tablets can be used in patients pre-treatedwith corticosteroids, in those who are refractory to treatment or incorticoid naïve patients.

Prednisone delayed-release tablets can be used as monotherapy or morelikely in combination with DMARDs, NSAIDs, TNF a Inhibitors and/oranalgetics.

Prednisone delayed-release tablets can be used for short, mid orlong-term treatment.

LITERATURE REFERENCES

-   ACR (American College of Rheumatology) Subcommittee on Rheumatoid    Arthritis Guidelines. Guidelines for the management of rheumatoid    arthritis. Arthritis Rheum 2002; 46:328-46.-   Ahlmén M, Nordenskiöld U, Archenholtz B, Thyberg I, Rönnqvist R,    Lindén L, et al. Rheumatology outcomes: the patient's perspective. A    multicentre focus group interview study of Swedish rheumatoid    arthritis patients. Rheumatology 2005; 44:105-10.-   Arnett F C, Edworthy S M, Bloch D A, McShane D J, Fries J F, Cooper    NS, et al. The American Rheumatism Association 1987 revised criteria    for the classification of rheumatoid arthritis. Arthritis Rheum    1988; 31:315-24.-   Arvidson N G, Gudbjörnsson B, Elfman L, Rydén A C, Tötterman T H,    Hällgren R. Circadian rhythm of serum interleukin-6 in rheumatoid    arthritis. Ann Rheum Dis 1994; 53:521-4.-   Arvidson N G, Gudbjörnsson B, Larsson A, Hällgren R. The timing of    glucocorticoid administration in rheumatoid arthritis. Ann Rheum Dis    1997; 56:27-31.-   Bijlsma J W J, Boers M, Saag K G, Furst D E. Glucocorticoids in the    treatment of early and late RA. Ann Rheum Dis 2003; 62:1033-7.-   Bijlsma J W J, Saag, KG, Buttgereit F, da Silva J A P. Developments    in glucocorticoid therapy. Rheum Dis Clin N Am 2005; 31:1-17.-   Boers M. Glucocorticoids in rheumatoid arthritis: a senescent    research agenda on the brink of rejuvenation? Best Practice Research    Clin Rheumatol 2004; 18 (1):21-9.-   Buttgereit F, Burmester G-R, Lipworth B J. Optimised glucocorticoid    therapy: the sharpening of an old spear. Lancet 2005; 365:801-3.-   Buttgereit F, Saag K G, Cutolo M, da Silva J A P, Bijlsma J W J. The    molecular basis for the effectiveness, toxicity, and resistance to    glucocorticoids: focus on the treatment of rheumatoid arthritis.    Scand J Rheumatol 2005; 34:14-21.-   Buttgereit F, Straub R H, Wehling M, Burmester G R. Glucocorticoids    in the treatment of rheumatic diseases: an update on the mechanisms    of action. Arthritis Rheum 2004; 50:3408-17.-   Capell H A, Madhok R, Hunter J A, Porter D, Morrison E, Larkin J, et    al. Lack of radiological and clinical benefit over two years of low    dose prednisolone for rheumatoid arthritis: results of a randomised    controlled trial. Ann Rheum Dis 2004; 63:797-803.-   Carr A, Hewlett S, Hughes R, Mitchell H, Ryan S, Carr M, et al.    Rheumatology outcomes: the patient's perspective. J Rheumatol 2003;    30:880-3.-   Conn D L. Resolved: Low-dose prednisone is indicated as a standard    treatment in patients with rheumatoid arthritis. Arthritis Rheum    2001; 45:462-7.-   Crofford L J, Kalogeras K T, Mastorakos G, Magiakou M A, Wells J,    Kanik K S, et al. Circadian relationships between interleukin (IL)-6    and hypothalamic-pituitary-adrenal axis hormones: failure of IL-6 to    cause sustained hypercortisolism in patients with early untreated    rheumatoid arthritis. J Clin Endocrinol Metab 1997; 82:1279-83.-   Cutolo M, Maestroni G J M, Otsa K, Aakre O, Villaggio B, Capellino    S, et al. Circadian melatonin and cortisol levels in rheumatoid    arthritis patients in winter time: a north and south Europe    comparison. Ann Rheum Dis 2005; 64:212-6.-   Cutolo M, Masi A T. Circadian rhythms and arthritis. Rheum Dis Clin    N Am 2005; 31:115-29.-   Cutolo M, Seriolo B, Craviotto C, Pizzorni C, Sulli A. Circadian    rhythms in RA. Ann Rheum Dis 2003; 62:593-6.-   Da Silva J A P, Jacobs J W G, Kirwan J R, Boers M, Saag K G, Ines L    B S, et al. Safety of low dose glucocorticoid treatment in    rheumatoid arthritis: published evidence and prospective trial data.    Ann Rheumatol Dis 2006; 65:285-93.-   Gudbjörnsson B, Skogseid B, Öberg K, Wide L, Hällgren R. Intact    adrenocorticotropic hormone secretion but impaired cortisol response    in patients with active rheumatoid arthritis. Effect of    glucocorticoids. J Rheumatol 1996; 23:596-602.-   Heshmati H M, Riggs B L, Burritt M F, McAlister C A, Wollan P C,    Khosla S. Effects of the circadian variation in serum cortisol on    markers of bone turnover and calcium homeostasis in normal    postmenopausal women. J Clin Endocrinol Metab 1998; 83:751-6.-   Hewlett S, Carr M, Ryan S, Kirwan J, Richards P, Carr A, et al.    Outcomes generated by patients with rheumatoid arthritis: How    important are they? Musculoskeletal Care 2005; 3:131-42.-   Hickling P, Jacoby R K, Kirwan J R. Joint destruction after    glucocorticoids are withdrawn in early rheumatoid arthritis.    Arthritis and Rheumatism Council Low Dose Glucocorticoid Study    Group. Br J Rheumatol 1998; 37:930-6.-   Hudson M, Baron M. Morning stiffness is a better predictor of    function in early inflammatory arthritis than are swollen and tender    joints. Arthritis Rheum 2005; 52 Suppl 9: abstract 1036.-   Jacobs J W G, van Everdingen A A, Verstappen S M M, Bijlsma J W J.    Followup radiographic data on patients with rheumatoid arthritis who    participated in a two-year trial of prednisone therapy or placebo.    Arthritis Rheum 2006; 54:1422-8.-   Karatay S. et al, The timing of low dose glucocorticoid therapy in    the treatment of rheumatoid arthritis, The Pain Clinic, 2002, 13, 4,    305-312-   Kirwan J R. The effect of glucocorticoids on joint destruction in    rheumatoid arthritis. The Arthritis and Rheumatism Council Low-Dose    Glucocorticoid Study Group. N Engl J Med 1995; 333:142-6.-   Kirwan J R, Boers M, Shea B. Glucocorticoids strongly suppress joint    damage in rheumatoid arthritis: A meta-analysis of 1, 414 patients    in 15 trials. Arthritis Rheum 2005; 52 Suppl 9: abstract 891.-   LeLoet X et al, Clinical practice decision tree for the coice of the    first disease modifying antirheumatic drug for very early rheumatoid    arthritis: a 2004 proposal of the French Society of Rheumatology,    Annals of Rheum Dis 2006; 65:45-50-   Mastorakos G, Ilias I. Relationship between interleukin-6 (IL-6) and    hypothalamic-pituitary-adrenal axis hormones in rheumatoid    arthritis. Z Rheumatol 2000; 59(Suppl 2):75-9.-   Petrovsky N, McNair P, Harrison LC. Diurnal rhythms of    pro-inflammatory cytokines: regulation by plasma cortisol and    therapeutic implications. Cytokine 1998; 10:307-12.-   Pincus T, Sokka T, Kautiainen H. Patients seen for standard    rheumatoid arthritis care have significantly better articular,    radiographic, laboratory, and functional status in 2000 than    in 1985. Arthritis Rheum 2005; 52:1009-19.-   Saag K G, Criswell L A, Sems K M, Nettleman M D, Kolluri S. Low-dose    corticosteroids in rheumatoid arthritis—A meta-analysis of their    moderate-term effectiveness. Arthritis Rheum 1996; 39:1818-25.-   Saag K G, Koehnke R, Caldwell J R, Brasington R, Burmeister L F,    Zimmerman B, et al. Low dose long-term corticoid therapy in    rheumatoid arthritis: an analysis of serious adverse events. Am J    Med 1994; 96:115-23.-   Stucki G, Cieza A. The international classification of functioning,    disability and health (ICF) core sets for rheumatoid arthritis: a    way to specify functioning. Ann Rheum Dis 2004; 63(Suppl 2):40-5.-   Svensson B, Boonen A, Albertsson K, van der Heijde D, Keller C,    Hafström J. Low-dose prednisolone in addition to the initial    disease-modifying antirheumatic drug in patients with early active    rheumatoid arthritis reduces joint destruction and increases the    remission rate: a two-year randomized trial. Arthritis Rheum 2005;    52:3360-70.-   van Everdingen A A, Jacobs J W G, Siewertsz van Reesema D R, Bijlsma    J W J. Low-dose prednisone therapy for patients with early active    rheumatoid arthritis: clinical efficacy, disease-modifying    properties, and side effects. A randomized, double-blind,    placebo-controlled clinical trial. Ann Intern Med 2002; 136:1-12.-   van Staa T P, Leufkens H G M, Abenhaim L, Zhang B, Cooper C. Oral    corticosteroids and fracture risk: relationship to daily and    cumulative doses. Rheumatology 2000; 39:1383-9.-   Wassenberg S, Rau R, Steinfeld P, Zeidler H. Very low-dose    prednisolone in early rheumatoid arthritis retards radiographic    progression over two years. Arthritis Rheum 2005; 52:3371-80.

1. A method for the treatment of a patient suffering from signs andsymptoms of an underlying rheumatic disease and/or osteoarthritis, whichcomprises administering to said patient an effective amount of aglucocorticoid contained in a delayed-release dosage form, wherein saidtreatment is administered once daily for at least about two weeks. 2.The method of claim 1, wherein the treatment comprises administration ofthe glucocorticoid for at least about four weeks.
 3. The method of claim2, wherein the treatment comprises administration of the glucocorticoidfor at least about eight weeks.
 4. The method of claim 3, wherein thetreatment comprises administration of the glucocorticoid for at leastabout twelve weeks.
 5. The method of claim 4, wherein the treatmentcomprises administration of the glucocorticoid for at least about twelvemonths.
 6. The method of claim 1, wherein the glucocorticoid dose isgreater than about 10 mg/day of prednisone, or an equivalent amount ofanother glucocorticoid, at the initiation of the therapy.
 7. The methodof claim 1, wherein the glucocorticoid dose is equal or less than about10 mg/day of prednisone, or an equivalent amount of anotherglucocorticoid, for maintenance therapy.
 8. The method of claim 1,wherein the rheumatic disease is rheumatoid arthritis, ankylosatingspondylitis and/or polymyalgia rheumatica.
 9. The method of claim 1,wherein said patient has not previously been treated with an oralimmediate release glucocorticoid, a NSAID, a DMARD, a TNFα inhibitor, anIL-1 inhibitor, an IL-6 inhibitor, an analgetic agent, or combinationsthereof.
 10. The method of claim 1, wherein said patient has previouslyundergone treatment with an agent selected from a oral immediate releasedosage form of a glucocorticoid, a NSAID, a DMARD, a TNFα inhibitor, anIL-1 inhibitor, an IL-6 inhibitor, an analgetic agent, or combinationsthereof.
 11. The method of claim 10, wherein said patient is refractoryto said treatment with an oral immediate release dosage form of aglucocorticoid.
 12. The method of claim 10, wherein the immediaterelease dosage form of a glucocorticoid is replaced by the delayedrelease dosage form.
 13. The method of claim 1, which further comprisesadministering to said patient an effective amount of a NSAID, a DMARD, aTNFα inhibitor, an IL-1 inhibitor, an IL-6 inhibitor, an analgeticagent, or combinations thereof.
 14. The method of claim 1, wherein saidtreatment consists essentially of administering to said patient aneffective amount of a glucocorticoid contained in a delayed-releasedosage form, wherein said treatment is administered once daily for atleast about two weeks.
 15. The method of claim 1, wherein thedelayed-release dosage form has a lag time of from about 2 hours toabout 6 hours after administration.
 16. The method of claim 1, whereinthe delayed-release dosage form has a lag time of from about 3 hours toabout 5 hours after administration.
 17. The method of claim 1, whereinthe delayed-release dosage form has a dissolution time of equal to orless than about 2 hours after the lag time is reached.
 18. The method ofclaim 1, wherein the delayed-release dosage form has a drug releasebehaviour which is independent of pH.
 19. The method of claim 1, whereinthe delayed release dosage form is a tablet or a capsule.
 20. The methodof claim 1, wherein the delayed-release dosage form comprises anon-soluble/non-swellable coating and a core comprising the active agentand a disintegrant and/or a swelling agent.
 21. The method of claim 1,wherein the glucocorticoid is cortisone, hydrocortisone, prednisone,prednisolone, methylprednisolone, budesonide, dexamethasone,fludrocortisone, fluocortolone, cloprednole, deflazacort, triamcinolone,or the corresponding pharmaceutically acceptable salts and/or estersthereof.
 22. The method of claim 21, wherein the glucocorticoid isprednisone, prednisolone, methylprednisolone, dexamethasone,fluocortolone, cloprednole, and deflazacort or the correspondingpharmaceutically acceptable salts and/or esters thereof.
 23. The methodof claim 1, wherein said delayed-release dosage form is effective at alower dose of glucocorticoid as compared to the administration of saidglucocorticoid in an immediate release dosage form.
 24. The method ofclaim 1, wherein said patient suffers from inflammation.
 25. The methodof claim 1, wherein the glucocorticoid is administered in the evening.26. The method of claim 25, wherein the glucocorticoid is administeredbetween about 9:00 pm and about 11:00 pm.
 27. A method for the treatmentof a patient suffering from morning stiffness and pain due to anunderlying rheumatic disease and/or osteoarthritis, which comprisesadministering to said patient an effective amount of a glucocorticoidcontained in a delayed-release dosage form, wherein said treatment isadministered once daily for at least about two weeks.
 28. The method ofclaim 27, wherein the treatment comprises administration of theglucocorticoid for at least about four weeks.
 29. The method of claim27, wherein the treatment comprises administration of the glucocorticoidfor at least about eight weeks.
 30. The method of claim 27, wherein thetreatment comprises administration of the glucocorticoid for at leastabout twelve weeks.
 31. The method of claim 27, wherein the treatmentcomprises administration of the glucocorticoid for at least about twelvemonths.
 32. The method of claim 27, wherein the glucocorticoid dose isgreater than about 10 mg/day of prednisone, or an equivalent amount ofanother glucocorticoid, at the initiation of the therapy.
 33. The methodof claim 27, wherein the glucocorticoid dose is equal or less than about10 mg/day of prednisone, or an equivalent amount of anotherglucocorticoid, for maintenance therapy.
 34. The method of claim 27,wherein the rheumatic disease is rheumatoid arthritis, ankylosatingspondylitis and/or polymyalgia rheumatica.
 35. The method of claim 27,wherein said patient has not previously been treated with an oralimmediate release glucocorticoid, a NSAID, a DMARD, a TNFα inhibitor, anIL-1 inhibitor, an IL-6 inhibitor, an analgetic agent, or combinationsthereof.
 36. The method of claim 27, wherein said patient has previouslyundergone treatment with an agent selected from a oral immediate releasedosage form of a glucocorticoid, a NSAID, a DMARD, a TNFα inhibitor, anIL-1 inhibitor, an IL-6 inhibitor, an analgetic agent, or combinationsthereof.
 37. The method of claim 36, wherein said patient is refractoryto said treatment with an oral immediate release dosage form of aglucocorticoid.
 38. The method of claim 36, wherein the immediaterelease dosage form of a glucocorticoid is replaced by the delayedrelease dosage form.
 39. The method of claim 27, which further comprisesadministering to said patient an effective amount of a NSAID, a DMARD, aTNFα inhibitor, an IL-1 inhibitor, an IL-6 inhibitor, an analgeticagent, or combinations thereof.
 40. The method of claim 27, wherein saidtreatment consists essentially of administering to said patient aneffective amount of a glucocorticoid contained in a delayed-releasedosage form, wherein said treatment is administered once daily for atleast about two weeks.
 41. The method of claim 27, wherein thedelayed-release dosage form has a lag time of from about 2 hours toabout 6 hours after administration.
 42. The method of claim 27, whereinthe delayed-release dosage form has a lag time of from about 3 hours toabout 5 hours after administration.
 43. The method of claim 27, whereinthe delayed-release dosage form has a dissolution time of equal to orless than about 2 hours after the lag time is reached.
 44. The method ofclaim 27, wherein the delayed-release dosage form has a drug releasebehaviour which is independent of pH.
 45. The method of claim 27,wherein the delayed release dosage form is a tablet or a capsule. 46.The method of claim 27, wherein the delayed-release dosage formcomprises a non-soluble/non-swellable coating and a core comprising theactive agent and a disintegrant and/or a swelling agent.
 47. The methodof claim 27, wherein the glucocorticoid is cortisone, hydrocortisone,prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone,fludrocortisone, fluocortolone, cloprednole, deflazacort, triamcinolone,or the corresponding pharmaceutically acceptable salts and/or estersthereof.
 48. The method of claim 47, wherein the glucocorticoid isprednisone, prednisolone, methylprednisolone, dexamethasone,fluocortolone, cloprednole, and deflazacort and the correspondingpharmaceutically acceptable salts and/or esters thereof.
 49. The methodof claim 27, wherein said delayed-release dosage form is effective at alower dose of glucocorticoid as compared to the administration of saidglucocorticoid in an immediate release dosage form.
 50. The method ofclaim 27, wherein said patient suffers from inflammation.
 51. The methodof claim 27, wherein the glucocorticoid is administered in the evening.52. The method of claim 51, wherein the glucocorticoid is administeredbetween about 9:00 pm and about 11:00 pm.
 53. A method for the treatmentof a patient having circadian fluctuations in Interleukin 6 levels dueto underlying inflammation, which comprises administering to saidpatient an effective amount of a glucocorticoid contained in adelayed-release dosage form, wherein said treatment is administered oncedaily for at least about two weeks, and wherein said treatment isadministered such that the glucocorticoid is released at or before thetime when the patient's Interleukin 6 level is at a daily peak.
 54. Themethod of claim 53, wherein said peak Interleukin 6 level occurs duringthe night.
 55. The method of claim 53, wherein the fluctuatingInterleukin 6 levels are caused by a rheumatic disease or asthma. 56.The method of claim 55, wherein the rheumatic disease is selected fromthe group consisting of rheumatoid arthritis, ankylosating spondylitis,polymyalgia rheumatica, asthma and combinations thereof.
 57. The methodof claim 53, wherein the treatment comprises administration of theglucocorticoid for at least about four weeks.
 58. The method of claim53, wherein the treatment comprises administration of the glucocorticoidfor at least about eight weeks.
 59. The method of claim 53, wherein thetreatment comprises administration of the glucocorticoid for at leastabout twelve weeks.
 60. The method of claim 53, wherein the treatmentcomprises administration of the glucocorticoid for at least about twelvemonths.
 61. The method of claim 53, wherein the glucocorticoid dose isgreater than about 10 mg/day of prednisone, or an equivalent amount ofanother glucocorticoid, at the initiation of the therapy.
 62. The methodof claim 53, wherein the glucocorticoid dose is equal or less than about10 mg/day of prednisone, or an equivalent amount of anotherglucocorticoid, for maintenance therapy.
 63. The method of claim 53,wherein said patient has not previously been treated with an oralimmediate release glucocorticoid, a NSAID, a DMARD, a TNFα inhibitor, anIL-1 inhibitor, an IL-6 inhibitor, an analgetic agent, or combinationsthereof.
 64. The method of claim 53, wherein said patient has previouslyundergone treatment with an agent selected from a oral immediate releasedosage form of a glucocorticoid, a NSAID, a DMARD, a TNFα inhibitor, anIL-1 inhibitor, an IL-6 inhibitor, an analgetic agent, or combinationsthereof.
 65. The method of claim 64, wherein said patient is refractoryto said treatment with an oral immediate release dosage form of aglucocorticoid.
 66. The method of claim 64, wherein the immediaterelease dosage form of a glucocorticoid is replaced by the delayedrelease dosage form.
 67. The method of claim 53, which further comprisesadministering to said patient an effective amount of a NSAID, a DMARD, aTNFα inhibitor, an IL-1 inhibitor, an IL-6 inhibitor, an analgeticagent, or combinations thereof.
 68. The method of claim 53, wherein saidtreatment consists essentially of administering to said patient aneffective amount of a glucocorticoid contained in a delayed-releasedosage form, wherein said treatment is administered once daily for atleast about two weeks.
 69. The method of claim 53, wherein thedelayed-release dosage form has a lag time of from about 2 hours toabout 6 hours after administration.
 70. The method of claim 53, whereinthe delayed-release dosage form has a lag time of from about 3 hours toabout 5 hours after administration.
 71. The method of claim 53, whereinthe delayed-release dosage form has a dissolution time of equal to orless than about 2 hours after the lag time is reached.
 72. The method ofclaim 53, wherein the delayed-release dosage form has a drug releasebehaviour which is independent of pH.
 73. The method of claim 53,wherein the delayed release dosage form is a tablet or a capsule. 74.The method of claim 53, wherein the delayed-release dosage formcomprises a non-soluble/non-swellable coating and a core comprising theactive agent and a disintegrant and/or a swelling agent.
 75. The methodof claim 53, wherein the glucocorticoid is cortisone, hydrocortisone,prednisone, prednisolone, methylprednisolone, budesonide, dexamethasone,fludrocortisone, fluocortolone, cloprednole, deflazacort, triamcinolone,or the corresponding pharmaceutically acceptable salts and/or estersthereof.
 76. The method of claim 75, wherein the glucocorticoid isprednisone, prednisolone, methylprednisolone, dexamethasone,fluocortolone, cloprednole, and deflazacort or the correspondingpharmaceutically acceptable salts and/or esters thereof.
 77. The methodof claim 53, wherein said delayed-release dosage form is effective at alower dose of glucocorticoid as compared to the administration of saidglucocorticoid in an immediate release dosage form.
 78. The method ofclaim 53, wherein the glucocorticoid is administered in the evening. 79.The method of claim 78, wherein the glucocorticoid is administeredbetween about 9:00 pm and about 11:00 pm.